Processes for the preparation of antiviral 7-azaindole derivatives

ABSTRACT

Provided are processes and synthetic intermediates useful for the preparation of azaindole piperazine diamide derivatives of the formula 
     
       
         
         
             
             
         
       
     
     These azaindole piperazine diamide derivatives, among other things, are useful as therapeutic agents for the treatment of HIV and AIDS.

This application claims a benefit of priority from U.S. ProvisionalApplication No. 60/367,401, the entire disclosure of which is hereinincorporated by reference.

The present invention relates to processes for the preparation ofcertain 7-azaindole compounds. More particularly the invention relatesto azaindole piperazine diamide derivatives that possess antiviralactivity. In addition, the invention relates to certain substitutedazaindole synthetic intermediates useful for, among other things, thepreparation of agents for the treatment of HIV and AIDS.

One useful therapeutic approach for the treatment of HIV and AIDSutilizes antiviral agents that target and inhibit HIV-1 reversetranscriptase. Often these reverse transcriptase inhibitors areadministered to patients in combination with antiviral agents thattarget other viral proteins, such as HIV protease. Non-nucleosidereverse transcriptase inhibitors (NNRTIs) have recently gained anincreasingly important role in the therapy of HIV infections (Pedersonet al., Antiviral Chem. Chemother. 1999, 10, 285–314).

One of the more effective classes of these non-nucleoside inhibitors areazaindole derivatives which are disclosed in copending U.S. patentapplication Ser. No. 09/912,710, filed Jul. 25, 2001. Among theazaindoles disclosed in the application are certain4-alkoxy-7-azaindoles that have an (N-aroylpiperazin-N′-yl)oxoacetylmoiety at the 3-position. For example, the compound,(R)-N-(benzoyl)-3-methyl-N′-[(4-methoxy-7-azaindol-3-yl)-oxoacetyl]-piperazine7a is an effective reverse transcriptase inhibitor and antiviral agentof this class.

Syntheses of 7a and related analogs have been described in copendingU.S. patent application Ser. No. 09/912,710. In procedures describedtherein for the preparation ofN-(aroyl)-N′-[(4-alkoxy-7-azaindol-3-yl)-oxoacetyl]-piperazines, theperipheral substituents on the heterocycle are typically introduced byaddition of the oxoacetyl substituent to the 3-position of theheterocyclic nucleus, followed by introduction of the alkoxy substituentto the 4-position. While these procedures are suitable for thepreparation of working quantities of these 7-azaindole analogs,alternative synthetic procedures for the preparation ofN-(aroyl)-N′-[(4-alkoxy-7-azaindol-3-yl)-oxoacetyl]-piperazines moreamenable to scale-up are desirable.

SUMMARY OF THE INVENTION

In one embodiment, the invention relates to a process for thepreparation of a compound of the formula

wherein

R¹, R³ and R⁴ are each independently selected from the group consistingof H, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl,C₂–C₆ alkynyl, halogen, cyano, phenyl, C(O)R⁵, C(O)NR⁸R⁹, OR¹⁰, SR¹¹,and NR¹²R¹³;

R⁵ is selected from the group consisting of H, C₁–C₆ alkyl, C₃–C₆cycloalkyl, C₂–C₆ alkenyl, and C₄–C₆ cycloalkenyl;

R⁸ and R⁹ are each independently selected from the group consisting ofC₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₃–C₆ alkenyl, C₄–C₆ cycloalkenyl andC₃–C₆ alkynyl; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₃–C₆ alkenyl or the carbon-carbontriple bond of said C₃–C₆ alkynyl are not the point of attachment to thenitrogen to which R⁸ or R⁹ is attached;

R¹⁰ and R¹¹ are each independently selected from the group consisting ofC₁–C₆ alkyl, C₁–C₆ alkyl substituted with one to three halogen atoms,C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl and C₃–C₆ alkynyl;provided the carbon atoms which comprise said carbon-carbon triple bondof said C₃–C₆ alkynyl are not the point of attachment to the oxygen orsulfur to which R¹⁰ or R¹¹ is attached;

R¹² and R¹³ are each independently selected from the group consisting ofC₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₃–C₆ alkenyl, C₄–C₆ cycloalkenyl andC₃–C₆ alkynyl; and C(O)R¹⁴; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₃–C₆ alkenyl, C₄–C₆ cycloalkenyl orthe carbon-carbon triple bond of said C₃–C₆ alkynyl are not the point ofattachment to the nitrogen to which R¹² or R¹³ is attached;

R¹⁴ is selected from the group consisting of H, C₁–C₆ alkyl, C₃–C₆cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl and C₂–C₆ alkynyl;

R⁶ is selected from the group consisting of H, C₁–C₆ alkyl, C₃–C₆cycloalkyl, C₄–C₆ cycloalkenyl, C(O)NR¹⁶R¹⁷, benzyl, C₃–C₆ alkenyl andC₃–C₆ alkynyl; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₃–C₆ alkenyl or the carbon-carbontriple bond of said C₃–C₆ alkynyl are not the point of attachment to thenitrogen to which R⁶ is attached;

R¹⁶ and R¹⁷ are each independently selected from the group consisting ofH, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₃–C₆ alkenyl, C₅–C₆ cycloalkenyl andC₃–C₆ alkynyl; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₃–C₆ alkenyl, C₅–C₆ cycloalkenyl orthe carbon-carbon triple bond of the C₃–C₆ alkynyl are not the point ofattachment to the nitrogen to which R¹⁶ and R¹⁷ are attached;

R⁷ is selected from the group consisting of CH₃, CH₂CH₃, CH₂CF₃ andCH₂CH₂CH₃;

R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷ and R²⁸ are each independentlyselected from the group consisting of H, C₁–C₆ alkyl, C₃–C₆ cycloalkyl,C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl, C₂–C₆ alkynyl, CR²⁹R³⁰OR³¹, C(O)R³²,CR³³(OR³⁴)OR³⁵, CR³⁶NR³⁷R³⁸, C(O)OR³⁹, C(O)NR⁴⁰R⁴¹, CR⁴²R⁴³F, CR⁴⁴F₂,and CF₃;

R²⁹, R³⁰ R³¹, R³², R³³, R³⁶, R⁴², R⁴³ and R⁴⁴ are each independentlyselected from the group consisting of H, C₁–C₆ alkyl, C₃–C₆ cycloalkyl,C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl, C₂–C₆ alkynyl and C(O)R⁴⁵;

R³⁴, R³⁵ and R³⁹ are each independently selected from the groupconsisting of H, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₃–C₆ alkenyl, C₄–C₆cycloalkenyl, and C₃–C₆ alkynyl; provided the carbon atoms whichcomprise the carbon-carbon triple bond of said C₃–C₆ alkynyl are not thepoint of attachment to the oxygen to which R³⁵ and R³⁹ are attached;

R³⁷ and R³⁸ are each independently selected from the group consisting ofH, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₃–C₆ alkenyl, C₄–C₆ cycloalkenyl andC₃–C₆ alkynyl; provided the carbon atoms which comprise thecarbon-carbon triple bond of said C₃–C₆ alkynyl are not the point ofattachment to the nitrogen to which R³⁷ and R³⁸ are attached;

R⁴⁰ and R⁴¹ are each independently selected from the group consisting ofH, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl andC₃–C₆ alkynyl; provided the carbon atoms which comprise thecarbon-carbon triple bond of said C₃–C₆ alkynyl are not the point ofattachment to the nitrogen to which R⁴⁰ and R⁴¹ are attached;

R⁴⁵ is selected from the group consisting of H, C₁–C₆ alkyl, C₃–C₆cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl, and C₂–C₆ alkynyl;

Ar is selected from the group consisting of

A¹, A², A³, A⁴, A⁵, B¹, B², B³, B⁴, C¹, C², C³, D¹, D² and D³ are eachselected from the group consisting of H, cyano, halogen, nitro, C₁–C₆alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl, C₂–C₆alkynyl, OR⁴⁶, NR⁴⁷R⁴⁸, SR⁴⁹, N₃ and CH(—N═N—)—CF₃;

R⁴⁶ is selected from the group consisting of H, C₁–C₆ alkyl, C₃–C₆cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl, C₂–C₆ alkynyl; providedthe carbon atoms which comprise the carbon-carbon triple bond of saidC₂–C₆ alkynyl are not the point of attachment to the nitrogen to whichR⁴⁶ is attached;

R⁴⁷ and R⁴⁸ are each independently selected from the group consisting ofH, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₃–C₆ alkenyl, C₅–C₆ cycloalkenyl,C₃–C₆ alkynyl, and C(O)R⁵¹; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₅–C₆ alkenyl, C₄–C₆ cycloalkenyl, orthe carbon-carbon triple bond of said C₃–C₆ alkynyl are not the point ofattachment to the nitrogen to which R⁴⁷ and R⁴⁸ are attached;

R⁴⁹ is selected from the group consisting of H, C₁–C₆ alkyl, C₃–C₆cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl, C₃–C₆ alkynyl andC(O)R⁵⁰; provided the carbon atoms which comprise the carbon-carbontriple bond of said C₃–C₆ alkynyl are not the point of attachment to thesulfur to which R⁴⁷ is attached;

R⁵⁰ is C₁–C₆ alkyl or C₃–C₆ cycloalkyl; and

R⁵¹ is selected from the group consisting of H, C₁–C₆ alkyl and C₃–C₆cycloalkyl. The process includes the steps of:

(a) treating a compound of the formula

with a chlorinating agent selected from one of

(i) a compound of the formulaR^(a)SO₂Cl

wherein R^(a) is C₁–C₄ alkyl; trifluoromethyl; phenyl or naphthalene,which phenyl or napthalene can be substituted with one or more H, C₁–C₆alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl, C₂–C₆alkynyl, halogen, cyano, nitro, phenyl, C(O)R⁵, C(O)NR⁸R⁹, OR¹⁰;

(ii) a compound of the formulaR^(b)COCl

wherein R^(b) is C₁–C₄ alkyl; trihalomethyl; C(O)R⁵; phenyl ornaphthalene, which phenyl or naphthalene can be substituted with one ormore H, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆cycloalkenyl, C₂–C₆ alkynyl, halogen, cyano, nitro, phenyl, C(O)R⁵,C(O)NR⁸R⁹, OR¹⁰; or

(iii) a compound of the formula

wherein R^(c) is independently H, C₁–C₄ alkyl; trifluoromethyl; phenylor naphthalene, which naphthalene is substituted with one or more H,C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl, C₂–C₆alkynyl, halogen, cyano, phenyl and OR¹⁰; and

wherein R^(d) is H, C₁–C₄ alkyl; halogen; trifluoromethyl; phenyl ornaphthalene, which naphthalene is substituted with one or more H, C₁–C₆alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl, C₂–C₆alkynyl, halogen, cyano, phenyl and OR¹⁰; to give a compound of theformula

(b) reacting the compound of the formula 3 with a potassium alkoxide ofthe formulaR⁷O—K+.

to give a compound of the formula

(c) treating the compound of the formula 4 with a compound of theformula

wherein R²⁰ is C₁–C₆ alkyl, C₃–C₆ cycloalkyl, aryl[C₁–C₆]alkyl or arylin the presence of a Lewis acid to give a compound of the formula

(d) hydrolyzing the ester of the compound of the formula 5 to give acompound of the formula

and

(e) coupling the compound of the formula 6 with a compound of theformula

using an acyl activating reagent to give the compound of the formula 7.

In preferred embodiments of the process for preparing the compound ofthe formula 7, R⁷ is CH₃O. In a particularly preferred embodiment ofthis process R¹, R³, R⁴ and R⁶ are H.

In another embodiment, the invention relates to a process for preparinga compound of the formula

wherein R¹, R³, R⁴ and R⁶ are as described above, by chlorinating acompound of the formula

using one of the three chlorinating agents described above, i.e., asulfonyl chloride reagent of the formula R^(a)SO₂Cl, a chlorinatingagent of the formula R^(b)COCl, or a compound of the formula

In a preferred embodiment for preparing the compound of the formula 3,R¹ and R³ are H; R⁴ is H, halogen or cyano (with H being particularlypreferred); and R⁶ is H, methyl or allyl (with H being particularlypreferred).

In another embodiment, the invention relates to a process for preparinga compound of the formula

by treating a compound of the formula 3 with a potassium alkoxide of theformulaR⁷O—K+.In preferred embodiments of the process for preparing the compound ofthe formula 4, R¹ is H or C₁–C₃ alkyl; R³ is H; R⁴ is H, halogen, cyanoor C(O)R⁵ (wherein R⁵ is as described above); and R⁶ is H, C₁–C₃ alkyl,allyl or benzyl. In a particularly preferred embodiment of this processR³, R⁴and R⁶are H.

In another embodiment, the invention relates to a process for preparinga compound of the formula

wherein R¹, R³, R⁴, R⁶, R⁷ and R²⁰ are as described above, by treating acompound of the formula 4, with a chlorooxoacetate reagent of theformula

in the presence of a Lewis acid. Preferably R²⁰ is methyl.

In another aspect, the invention relates to certain compounds that areuseful, among other things, for preparing the compound of the formula 7.For example, the compounds of the formulas

are useful synthetic intermediates.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the invention, a compound of the formula 7, whereinR¹, R³, R⁴ and R⁶ are as described above can be obtained by thesynthetic sequence depicted in Scheme 1. In the sequence, the compoundof the formula 1 is initially elaborated to incorporate alkoxysubstituents at the 4-position of the heterocycle to provide thecompound of the formula 4. The 4-alkoxy substituent is introduced by wayof pyridine N-oxide formation, regioselective chlorination of the4-position, and nucleophilic displacement of the resultant chloride byan alkoxide. Next, an electrophilic acylation of the 3-position yields aglyoxylate ester intermediate, the compound of the formula 5. Hydrolysisof the ester and activation of the resultant carboxylic acid, yields anactivated carboxylic acid intermediate. The intermediate is then coupledwith an aroyl piperazine of the formula 8 to provide the compound of theformula 7. The ring positions specified herein may be referencedaccording to the following nomenclature:

While 7-azaindole, per se, is available from commercial sources,(Aldrich Chemical Co., Milwaukee, Wis.) other starting 7-azaindoles canbe prepared by methods described in the literature (Mahadevan et al. J.Heterocycl. Chem., 1992, 29, 359–367) or Hands et al. Synthesis 1996,866–882). These references and similar references show some examples ofthe preparation of substituted 7-azaindole compounds. It will beapparent to those of skill in the art that the general methodology canbe extended to azaindoles that have different substituents in thestarting materials. Azaindoles are also prepared via the routesdescribed in copending U.S. patent application Ser. No. 09/912,710,herein incorporated by reference in its entirety. Some of these routesare summarized in Schemes 2 and 3 (below), and in the accompanyingdiscussion.

In Scheme 2, the Bartoli indole synthesis (Dobson et al. Synth. Commun.1991, 21, 611–617) is extended to prepare substituted 7-azaindoles.Nitropyridine 9 is reacted with an excess of vinyl magnesium bromide at−78° C. After warming up to −20° C., the reaction provides the desired7-azaindole 1b. Generally these temperature ranges are effective but inspecific examples can be varied usually by no more than about 20° C. butoccasionally by more in order to optimize the yield. The vinyl magnesiumbromide can be obtained commercially as a solution in tetrahydrofuran orsometimes more optimally can be prepared fresh from vinyl bromide andmagnesium using literature procedures that are well known in the art.

In Scheme 3 (above), trimethylsilylacetylene is coupled onto ahalo-pyridine 10 using a Pd(0) catalyst to furnish 10. Subsequenttreatment with base effects cyclization of 11 to afford 7-azaindole 1b(Sakamoto et al. Chem. Pharm. Bull. 1987, 35, 1823–1828). Suitable basesfor the second step include sodium methoxide or other sodium, lithium orpotassium alkoxide bases.

The compound of the formula 1 wherein R⁶ is alkyl can be prepared bydeprotonation of N-1 of the compound 1b, and alkylation of the resultinganion with suitable alkyl halides, e.g., chlorides, bromides or iodides,preferably bromides or iodides. In an analogous manner, the compound ofthe formula 1 wherein R⁶ is cycloalkyl, cycloalkenyl, alkenyl or alkynylcan be prepared by reaction of the anion of the compound of the formula1b with the corresponding halides. Skilled chemists will recognize thatmesylates, tosylates and the like can be used in place of halides asalkylating agents. The deprotonation of the 7-azaindole 1b can beconducted using a strong base, e.g., alkali metal hydride, in an inertorganic solvent, e.g., tetrahydrofuran, dimethylformamide, attemperatures from about −78 to about 100° C.

In the process, the chloro compound of the formula 3 can be obtainedfrom the compound of the formula 1, via the N-oxide intermediate 2. Aswill be recognized by those of ordinary skill in the art, oxidation ofthe pyridine N-atom serves to render the 4-position of the heterocyclicnucleus susceptible to nucleophilic addition. The oxidation of thecompound of the formula 1 is conducted using an oxidizing agent such asa peracid, e.g., peracetic acid, meta-chloroperoxybenzoic acid (mCPBA),or hydrogen peroxide. Other oxidation reagents that could be used forthe pyridine N-oxide formation include hydrogen peroxide-urea reagent,magnesium monoperoxyphthalate hexahydrate, and potassiumperoxymonosulfate (Oxone®). Generally, the oxidation is conducted in apolar organic solvent such as acetone, DMF or ethyl acetate attemperatures of about −5 to 35° C., preferably at about roomtemperature.

In preferred embodiments the oxidation is conducted using a peracid,more preferably using mCPBA in ethyl acetate. The oxidation with mCPBAis typically performed using from about 1 to 3 equivalents of mCPBA,preferably about 1.05–1.4 equivalents. The product from the mCPBAtreatment is typically isolated as the meta-chlorobenzoic (mCBA) acidaddition salt. Treatment of the salt with aqueous base, e.g., aqueouspotassium carbonate liberates the free base 2 for use in the nextsynthetic step.

The compound of the formula 3, is obtained from the compound of formula2 by treatment with a chlorinating agent. The chlorinating reagent ispreferably one of: an alkyl/arylsulfonyl chloride of the formulaR^(a)SO₂Cl; an alkyl/aryl carboxylic acid chloride of the formulaR^(b)COCl; or a chloromethylene N,N-disubstituted ammonium chloride ofthe formula

wherein R^(a), R^(b), R^(c) and R^(d) are as described above. Applicantshave found that the use of these preferred chlorinating reagentsprovides the compound of the formula 3 with improved regioselectivityrelative to conventional chlorination procedures for 7-azaindoles. Forexample, treatment of the compound of the formula of the 2a withphosphorus oxychloride using a procedures similar to that described bySchneller et. al. in J. Org. Chem. 1980, 45, 4045–4048 led to mixturesof the desired 4-chloro isomer 2a and the 3-chloro isomer 12. Forexample, when the chlorination was conducted in toluene at 90 to 95° C.,then ratios of the 4-chloro isomer/3-chloro isomer ranged from 3:1 to9:1 (Scheme 4). Due to the less desirable product mixture in the crudeproduct, multiple recrystallizations were used to obtain the productwith acceptable isomeric purity (i.e., greater than 99:1). The multiplerecrystallizations of the product resulted in a lower overall yields ofthe purified product. Chlorination procedures that provide improvedregioselectivity are therefore preferable from the standpoint of bothoperational simplicity and improved overall yield.

In preferred embodiments the chlorination of 2 is conducted with analkyl or arylsulfonyl chloride of the formula R^(a)SO₂Cl. PreferablyR^(a) is methyl, phenyl or p-methylphenyl. More preferably R^(a) ismethyl. There is generally about 2 to 3 equivalents of the sulfonylchloride reagent present per mole of compound of the formula 2.Preferably however, at least 2.58 equivalents of the sulfonyl chloridereagent is used to achieve convenient reaction rates, with a range of2.58–2.75 equivalents being particularly preferred.

The chlorination reaction is typically conducted in a polar aproticsolvent such as dichloromethane, 2-methyltetrahydrofuran, butyl acetate,N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, toluene, orDMF. Preferably the solvent for the reaction is acetonitrile or DMF,with DMF being particularly preferred. Generally, the concentration ofcompound 2 in the reaction solvent is from about 1 to 2 M, with apreferred concentration of 1.25 to 1.33 M.

The reaction can be conducted at temperatures of about 45 to 90° C.,with preferred temperatures of about 50 to 75° C. While the reaction canbe carried out at higher temperatures, lower temperature are preferredfor improved regioselectivity.

The compound of the formula 4 can be formed by nucleophilic displacementof the chloro group with a potassium alkoxide of the formulaR⁷O—K+wherein R⁷ is CH₃, CH₂CH₃, CH₂CF₃ or CH₂CH₂CH₃. The alkoxide can begenerated by adding potassium metal to a solution of the parent alcohol.Alternatively the potassium alkoxide can be prepared by treatment of asolution of the parent alcohol with a strong potassium base, e.g.,potassium hydride, hexamethyldisilazide, diisopropylamide. In somecases, e.g., potassium methoxide and ethoxide, the potassium alkoxideare commercially available. In a preferred process, potassium methoxideis used.

In one preferred embodiment of the process, the alkoxide displacement isconducted in a slurry of a carbocyclic aromatic solvent and portions ofdiatomaceous earth (e.g., Celite®). Both the compound of the formula 3and potassium alkoxide have limited solubility in the reaction solvent.While not being bound by theory, Applicants believe that thediatomaceous earth acts as a phase transfer reagent that providessurface areas where the reaction can take place. In any case, improvedconversions are observed for process runs containing portions ofdiatomaceous earth. In contrast, in trials where diatomaceous earth wasomitted from the reaction mixtures, the mixtures contained a gummyresidue that was insoluble in the carbocyclic aromatic solvent, and poorconversions of compound of the formula 3, were observed.

Generally the alkoxide displacement in this preferred embodiment, isconducted at temperatures of from about 105 to 120° C., with preferredtemperatures of from about 105 to 110° C. Typically there are at least 2equivalents of the potassium alkoxide added per molar equivalent of 3.Preferably, from 2 to 5 equivalents of potassium alkoxide are used inthe process.

Preferred carbocyclic aromatic solvents for this alkoxide displacementstep include toluene, xylene and mesitylene, with toluene beingparticularly preferred. Generally, from about 15 to 40 mL, preferablyfrom about 18.5 to 30 mL of toluene is added per gram of the compound ofthe formula 3. In addition, from about 1 to 2 g, preferably from about1–1.5 g of diatomaceous earth is added per gram of the compound of theformula 3.

In another preferred embodiment of the process, the alkoxidedisplacement is conducted without any added diatomaceous earth. In thisdisplacement process, the compound of the formula 3 is treated with botha potassium alkoxide of the formulaR⁷O—K+and a lithium alkoxide of the formulaR⁷O—Li+,in a mixture of a carbocyclic aromatic solvent and t-butanol. Both theinclusion of lithium alkoxide and the cosolvent t-butanol improve thesolubility of the alkoxide in the reaction solvent to achieve practicalreaction rates and conversions. As this preferred process does notrequire a filtration step to remove the diatomaceous earth duringreaction workup, this process is particularly preferred for larger scaleprocesses where filtration steps are less convenient to implement.

In this diatomaceous earth-free embodiment, the carbocyclic aromaticsolvent is preferably xylene. The concentration of the compound of theformula 3 in the reaction is preferably less than 1.0 M, more preferablybetween 0.8 to 1.0 M. As the reaction mixture is typically a slurry,higher concentrations of 3 in the reaction lead to mixtures that are toothick for efficient stirring.

Preferred embodiments of the diatomaceous earth-free embodiment processutilize potassium methoxide in the displacement step. Typically, thereaction is conducted with about 2 to about 5 equivalents of potassiummethoxide, preferably about 2.2 to 4 equivalents per mole of 3. Inaddition, there is typically about 1 to 2 equivalents, preferably about1.5 to 2 equivalents, of lithium methoxide per mole of 3. The process isgenerally conducted at 110 to 125° C. with preferred temperatures of 114to 117° C.

The compound of the formula 5

can be prepared by adding a chlorooxoacetate reagent of the formula

wherein R²⁰ is an alkyl, cycloalkyl, arylalkyl or aryl group, to thecompound of the formula 4 in the presence of a Lewis Acid.

The crude product from this addition reaction may contain small amounts(e.g., less than 20%) of a diacylated product with a glyoxylate group atthe the N-1 position in addition to the glyoxylate group at C-3. Thepresence of the diacylated material in the reaction product generallyrequires no further purification steps, as the N-1 glyoxylate group iscleaved under the basic conditions used to hydrolyze the ester of theglyoxylate group at the C-3 position.

A number of Lewis acids can be used for the glyoxylate addition reactionincluding aluminum trichloride, tin (IV) chloride, ferric chloride andzirconium tetrachloride. Preferably, the Lewis acid used in thisglyoxylate addition reaction is aluminum trichloride. Typically, thereis at least 4 equivalents of aluminum trichloride used per mole of thecompound of the formula 4. Preferably, the reaction is performed using 4to 5 equivalents of aluminum trichloride per mole of the compound of theformula 4.

The glyoxylate addition is preferably conducted in a solvent mixture ofdichloromethane and a [C₁–C₃]nitroalkane (e.g., nitromethane,nitropropane) at temperatures of about 0 to 20° C. While the additionwill take place in a neat solution of the nitroalkane, due to safetyconcerns, a diluted solvent mixture of the nitroalkane anddichloromethane is preferred. Preferably the solvent mixture comprises anitroalkane and dichloromethane in a ratio of 4:1 to 17:3. A preferrednitroalkane solvent is nitromethane.

The glyoxylate ester moiety at the 3-position of the compound of theformula 5 is subsequently hydrolyzed to give the carboxylic acid of theformula 6.

The hydrolysis can be conducted using an aqueous base, e.g., sodium orpotassium hydroxide, at temperatures of about 10 to 30° C. Thecarboxylic acid of the formula 6, is preferably isolated as the freeacid after acidic workup. If higher purities are desired, the carboxylicacid of the formula 6 can be further purified by recrystallization fromsuitable solvents such as dimethylsulfoxide and water.

As will be apparent to those of ordinary skill in the art, in someembodiments of the process, the glyoxylate ester moiety of the formula 5may be susceptible to alternative cleavage conditions, such as acidic orreductive conditions. For example, acidic condition can be used tohydrolyze the ester in embodiments of the compound of the formula 5,wherein the glyoxylate ester is a t-butyl ester.

The compound of the formula 7

can then be prepared by coupling the carboxylic acid of the formula 6with an aroyl piperazine of the formula 8,

wherein R²¹–R²⁸ and Ar are as described above, using an acyl activatingagent. Acyl activating agents include reagents effective to prepare anacid chloride intermediate such as(chloromethylene)-N,N-dimethylammonium chloride (Vilsmeier reagent) oroxalyl chloride. Acyl activating agents also include reagents effectiveto prepare activated ester intermediates such as(3-diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT). Couplingprocedures utilizing DEPBT and acyl amides are described in copendingU.S. patent application Ser. No. 09/912,710.

The aroyl piperazine of the formula 8 can be prepared according to wellestablished procedures such as those described by Desai et al. (Org.Prep. Proced. Intl. 1976, 8, 85–86), Adamczyk et al. (Org. Prep. Proced.Intl. 1996, 28, 470–474), Rossen et al. (Tetrahedron Lett. 1995, 36,6419–6422) and Wang et al. (J. Org. Chem. 1999, 64, 7661–7662 and J.Org. Chem. 2000, 65, 4740–4742). Other examples for the preparation ofaroyl piperazines are described in WO 00/765271, herein incorporated byreference. For example, (R)-2-methyl-4-benzoyl piperazine amide 8a

can be prepared by treatment of (R)-2-methylpiperazine 13 (commerciallyavailable from Aldrich Chemical Company, Milwaukee, Wis.)

with an equimolar amount of methyl benzoate and dimethylaluminumchloride at room temperature.

The following examples further illustrate the present invention, but ofcourse, should not be construed as in any way limiting its scope.

EXAMPLE 1 Preparation of 1H-Pyrrolo[2,3-b]pyridine 1-oxide 2a

A solution of 1H-pyrrolo[2,3-b]pyridine (1a)

(2.973 kg) in ethyl acetate (22.562 kg) was cooled to 0 to 5° C. To thecooled solution was added a solution of mCPBA (6.872 kg, 1.22 eq) inethyl acetate (14.884 kg) over the course of about 1.5 h. The residualmCPBA was washed into the reaction mixture by an additional portion ofethyl acetate (5.933 kg). The resulting solution was warmed to 16 to 24°C., and allowed to stir at this temperature until the starting azaindolela had been consumed (as judged by reversed phase HPLC analysis). Thereaction mixture was then cooled to 0 to 10° C. The resulting slurry wasfiltered to collect the N-oxide as the meta-chlorobenzoic acid (m-CBA)addition salt 2a′.

The solid was washed with additional ethyl acetate and then dried toprovide 5.716 kg (78.2%) of 2a′.

The mCBA salt 2a′ was treated with aqueous base to liberate the N-oxide2a by the following procedure. A slurry of 2a′ (3.338 kg) in deionizedwater (14.105 kg) at 15 to 25° C. was treated with a sufficient amountof an aqueous solution containing 30% by weight K₂CO₃ to raise the pH ofthe slurry to about 9.5 to 10.5. Additional water (6.441 kg) was addedto the mixture, and the temperature maintained at 15 to 25° C. for 1 to2 h. The slurry was cooled to 0 to 5° C. for 1 to 5 h, and then filteredto recover the precipitate. The precipitate was washed with additionalwater. The precipitate was then dried to afford 1.258 kg of 2a.

EXAMPLE 2 Preparation of 4-Chloro-1H-pyrrolo[2,3-b]pyridine 3a

A solution of 2a (1.926 kg) in DMF (9.705 kg) was heated to about 50° C.Methanesulfonyl chloride (4.399 kg) was added to the heated solution atsuch a rate as to maintain the reaction temperature at 65 to 75° C. Theresulting mixture was heated at about 68 to 77° C. until the reactionwas judged complete by reversed phase HPLC analysis. The reactionmixture was cooled to about 30° C., and then quenched with water (31.024kg). Upon cooling the quenched reaction mixture to 5° C., sufficient 10N NaOH solution was added to raise the pH of the solution to about 7.The resulting slurry was warmed to 25° C., agitated for approximately 1h, and then filtered to collect the product. The product was washed withadditional water, and dried under high vacuum at 45 to 50° C. to afford1.904 kg of 3a.

EXAMPLE 3 Preparation of 4-Methoxy-1H-pyrrolo[2,3-b]pyridine

A flask equipped with a mechanical stirrer, temperature probe, condenserand Dean-Stark trap was charged with toluene (4.35 L), 3a (217.4 g) anddiatomaceous earth (Celite®, 326.1 g). Solid potassium methoxide wasadded and the resulting suspension was heated. Methanol was collected inthe Dean-Stark trap over the course of 1 h. The reaction mixture wasthen heated at reflux for about 27–29 h. The reaction mixture was cooledto about 80° C. and then water (4.022 L) was added. The suspension wascooled to about 20° C., and then the diatomaceous earth (containing theadsorbed product) was collected by filtration. The filter cake waswashed with water (2×217 mL) and then suctioned dry. The resultingfilter cake was triturated with CH₂Cl₂ (8.68 L) for 30 min. The mixturewas filtered and the filter cake was triturated with additional CH₂Cl₂(2×2.1 L). The CH₂Cl₂ extracts were combined and evaporated to dryness.The resulting concentrate was azeotroped with ethyl acetate (2×650 mL)to dryness. The concentrate was then triturated with ethyl acetate (650mL) at about 60° C. and then cooled to 0 to 5° C. The resulting slurrywas stirred for 1 h, and then filtered to collect the product. Theproduct was washed with additional cold ethyl acetate (105 mL) and driedat 35° C. to provide 135.2 g of 4a.

EXAMPLE 4 Alternative Preparation of 4-Methoxy-1H-pyrrolo[2,3-b]pyridine

A suspension of 3a (50 g, 0.32770 moles), potassium methoxide (91.94 g,4.0 equivalents, 1.31079 moles), lithium methoxide (24.89 g, 2.0equivalents, 0.65539 moles) in a mixture of xylene (300 mL) andt-butanol (37.5 mL) was heated at 116 to 117° C. for about 36 to 40 h.The reaction mixture was cooled to 40–50° C., and then water (826 mL)was slowly introduced. The resulting mixture was cooled to below 10° C.Sufficient concentrated HCl was added to raise the pH of the mixture to1.5 to 2.0, while maintaining the temperature of the mixture below 20°C. during the addition. The phases were separated. The aqueous layer(containing product) was washed with xylene (2×100 mL) to remove anyresidual starting material. Sufficient 10 N NaOH was added to raise thepH of the aqueous layer to 6.5–7.0. The resulting beige-colored slurrywas stirred at 5–10° C. for about 30 min. The product was collected byfiltration. The product was washed with cold water (260 mL) and thenheptane (240 mL). The product was dried at 55° C. in vacuo (25–30 in ofmercury) to provide 32.5 g (66.7 M %) of 4a.

In certain embodiments it may be preferable to recrystallize the product4a to provide a more purified product. The following procedureexemplifies recrystallizations that could be performed to purify 4a.

A slurry of crude 4a (34 g) in a mixture of n-butyl acetate (1.19 L) andwater (340 mL) was heated to 50° C. to effect dissolution of the solids.The resulting biphasic solution was cooled to 40° C. and the aqueouslayer was separated. The n-butyl acetate layer was concentrated toobtain a concentration of about 1 g crude 4a/10 mL mixture. Theresulting slurry was heated to 105° C. until all solids had dissolved,and then it was cooled to 40° C. over the course of 15 h. The slurry wasthen cooled to 0° C. over the course of 2 h. The product was collectedby filtration, washed with cold n-butyl acetate (60 mL) and thenn-heptane (120 mL). The product was dried at 45–50° C. to provide 29 g(85 M %).

EXAMPLE 5 Preparation of Methyl (4-methoxy-7-azaindol-3-yl)-oxoacetate

A mixture of 4a (131.17 g, 0.885 mole) and AlCl₃ (590.3 g, 4.427 mole)in CH₂Cl₂ (3935 mL) was cooled to 0 to 5° C. Nitromethane (918 mL) wasadded dropwise via addition funnel while maintaining the temperature ofthe mixture below 12° C. during the course of the addition. Methylchlorooxoacetate (203.5 mL, 2.213 moles) was then added dropwise viaaddition funnel while maintaining the temperature of the mixture below12° C. during the course of the addition. The reaction mixture wasstirred while being chilled by an ice bath for a total of 3 h. A chilled(0 to 5° C.) 2.5 M NH₄OAc solution was then added dropwise by additionfunnel to the reaction mixture while maintaining the temperature of thereaction mixture below 30° C. The biphasic mixture was separated. Theaqueous phase was extracted with additional CH₂Cl₂ (2×1 L). The organiclayers were combined and washed with water (1×1.5 L). The organic phasewas concentrated on a rotary evaporator to a volume of 2 L. Isopropylalcohol (2.7 L) was added to the concentrate, and the resulting mixturewas concentrated on the rotary evaporator to a volume of 2 L. Thecoevaporation procedure was repeated with an additional 2.7 L ofisopropyl alcohol. The resulting slurry was stirred for 16 h at roomtemperature. The product was collected by filtration. The filter cakewas washed with additional isopropyl alcohol (2×100 mL), and dried toprovide crude 5a (169.70 g). By ¹H NMR analysis the crude product was4–5/1 ratio of 5a and the corresponding N-1 acetate thereof. The crudeproduct was used without further purification in the next step.

EXAMPLE 6 Preparation of (4-methoxy-7-azaindol-3-yl)-oxoacetic acid

5a (223.7 g, 0.955 mole) was added to a 4N NaOH solution (1190 mL), andthe resulting mixture was stirred at 20 to 25° C. for 1 h. The reactionmixture was filtered to remove a very fine, red-colored solid. Theresulting filtrate was cooled and 1N HCl (3800 mL) was added. Theaddition was conducted at such a rate as to keep the reactiontemperature at or below 25° C. The resulting mixture was stirred about30 min and an additional portion (600 mL) of 1 N HCl was added to effecta final pH of 4.5 for the mixture. The resulting slurry was stirred foran additional 30 min. The product was collected by filtration, washedwith water (1×800 mL), and then acetone (2×400 mL). The product wasdried to yield 6a (195.6 g). The product 6a can be recrystallized fromdimethylsulfoxide and water if further purification is desired.

EXAMPLE 7 Preparation of(R)-N-(benzoyl)-3-methyl-N′-[(4-methoxy-7-azaindol-3-yl)-oxoacetyl]-piperazine7a

A solution of (chloromethylene)dimethyl ammonium chloride (Vilsmeierreagent, 19.20 g, 0.15 mole) in acetonitrile (600 mL) was prepared. 6a(22.02 g, 0.10 mole) was added to the reaction mixture along withadditional acetonitrile (25 mL). The reaction mixture (a yellow-coloredsuspension) was stirred for about 1 h to form the acid chlorideintermediate.

The suspension was cooled to −40° C., and a solution of 8a (24.5 g, 0.12mole), diisopropylethylamine (DIPEA, 69.8 mL, 4 equivalents) in ethylacetate (300 mL) was added dropwise to the suspension. The rate ofaddition was adjusted to maintain the reaction temperature below 35° C.The cooling bath was removed, and the resulting reaction mixture wasstirred at 20–25° C. for approximately 4 h. An aqueous solution of 17wt. % NaCl (800 mL) was added to the reaction mixture, and the resultingmixture was stirred vigorously for 15–20 min. The phases were separated.The organic phase was washed with aqueous 17 wt. % NaCl solution (2×400mL). The aqueous layers were combined, and extracted with ethyl acetate(3×220 mL). The organic layers were combined, washed with aqueous 20 wt.% NaHSO₃ solution (1×400 mL), and evaporated to dryness. The residue wasazeotroped with toluene (2×110 mL) at 50–55° C. to provide 42.17 g ofthe crude product 7a as a yellow-colored foam.

The product was recrystallized by dissolving the crude product inacetone (190 mL) and water (190 mL) at 55–60° C. The orange solution waspolish-filtered through a paper filter, and rinsed with additionalacetone/water 1:1 (42 mL). The resulting filtrate was warmed to 40° C.,seeded with authentic purified product, and then allowed to cool withstirring at 20–25° C. overnight. The resulting beige suspension waswarmed to 40–45° C. and stirred at 20–25° C. for about 24 h. Thesuspension was then cooled to room temperature, and stirred for 4 h,followed by cooling at 0–5° C. for 1 h. The resulting product wascollected by filtration, washed with ice cold acetone/water 1:1 (42 mL)and ice cold acetone (21 mL). The solid was dried at 60–65° C. underhigh vacuum to provide 25.9 g of 7a.

EXAMPLE 8 Screening of Chlorinating Agents for the Conversion of 2a to3a

Chlorinating reagents were screened to optimize the ratio of 4-Cl/3-Clisomers. 100 mg of the N-oxide 2a was utilized in each experiment.Toluene was added to a concentration of 20 mL/g of 2a. The reactionswere heated at 110° C. 2.3 Equivalents of chlorinating reagent per moleof 2a were used in each experiment.

Samples of each experiment were assayed by chromatography for the ratioof products. An aliquot from each sample was diluted in CH₃CN/H₂O (1:1).5 μL of each diluted sample was injected into the HPLC.

The HPLC used for the assay was equipped with a 3.9×150 mm C-18 column(5 μm, Waters WAT046980 column). The detector was set at λ=230 nm. Agradient elution profile was used:

Solvent A—95% water, 5% CH₃CN, 0.03% trifluoroacetic acid

Solvent B—5% water, 95% CH₃CN, 0.03% trifluoroacetic acid

The gradient was increased from 5% of Solvent B to 95% Solvent B overthe course of 25 minutes (End time=20 minutes, post run in 5 minutes).The results are shown in Table 1.

TABLE 1 un- 3,4- Ratio Starting known 3-chloro 4-chloro dichloro (4-Cl/Chlorinating material isomer isomer isomer isomer 3-Cl) Reagent 2a 15 123a 14 (3a/12) methane- 43.51 6.67 6.39 39.41 4.02 7.17 sulfonyl chlorideethanesulfonyl 83.82 2.41 1.21 10.57 2.99 9.76 chloride propane- 80.531.99 1.34 11.68 4.46 9.71 sulfonyl 1-chloride 1-butane- 52.92 3.93 3.1631.36 8.63 10.91 sulfonyl chloride trifluoro- 97.09 1.31 0.69 0.90 0.002.30 methane sulfonyl chloride benzene- 60.51 3.01 2.58 32.80 1.10 13.70sulfonyl chloride p- 63.03 2.70 3.06 29.89 1.31 10.76 toluenesulfonylchloride 4- 80.69 0.00 1.31 16.62 1.38 13.66 chlorobenzene- sulfonylchloride 4-methoxy 65.06 2.57 3.04 28.46 0.87 10.37 benzene- sulfonylchloride 4-nitro- 50.17 3.87 4.20 36.09 5.67 9.60 benzene- sulfonylchloride 2-naphthalene- 76.54 0.00 0.00 22.63 0.84 sulfonyl chlorideoxalyl chloride 95.84 1.91 1.33 0.93 0.00 1.70 methyl 68.86 3.38 5.3410.00 12.41 2.87 chloro- oxoacetate pivaloyl 72.49 17.28 5.93 1.91 2.391.32 chloride 4- 26.33 38.12 12.22 6.47 16.86 1.53 chlorobenzoylchloride 4-nitrobenzoyl 27.15 36.89 9.62 6.39 19.94 1.66 chloride3-(chloro- 29.00 11.32 8.42 4.75 46.51 1.56 methyl)- benzoyl chloridemethyl 97.65 0.73 0.18 0.19 1.25 2.07 choroformate Vilsmeier 5.95 0.4635.59 57.12 0.87 2.61 reagent Rt 3.11 4.83 6.93 7.37 11.52 RRt 0.4490.697 1.000 1.063 1.662

As can be seen from Table 1, among the chlorinating agents screened,methanesulfonyl chloride, benzenesulfonyl chloride and p-toluenesulfonylchloride showed promising results in terms of conversion and 4-Cl/3-Clratio.

EXAMPLE 9 Screening of Reaction Solvents for the Conversion of 2a to 3aUsing Methanesulfonyl Chloride as a Chlorinating Reagent

In this experiment, various solvents were screened using methanesulfonylchloride as the chlorinating reagents. In each experiment 2.5 molarequivalents of methanesulfonyl chloride per mole of 2a (500 mg) wereused. The reactions were heated at 70–80° C. for 1.5 h. Theconcentration was 20 mL of each solvent per gram of 2a. HPLC methodswere used to assay the products in the experiments. The HPLC conditionswere the same as those used in Example 7. The results are shown in Table2.

TABLE 2 Rt 2.98 5.39 8.14 8.66 11.09 12.62 RRt 0.34 0.62 0.94 1.00 1.281.46 unknown 3-Cl 4-Cl 3,4 di-Cl Ratio Run Solvent additive 2a 15 12 3a14 16 (3a/12) 1 Me-THF none 42.67 6.63 5.03 26.29 13.68 5.70 6.23 2Me-THF LiCl 34.86 7.16 12.85 36.25 7.18 1.69 3.82 (5 eq) 3 Isobutyl none58.43 5.43 4.81 20.10 8.13 3.10 5.18 acetate 4 CH₃CN none 35.88 4.735.06 49.17 1.64 3.53 10.72 5 Toluene none 57.24 4.02 2.91 23.79 8.223.81 9.18 6 ClCH₂CH₂Cl none 68.01 1.53 2.97 24.12 2.13 1.24 9.12

From the data presented in Table 2, it was observed that acetonitrilegave superior results in terms of both N-4/N-3 ratio, as well asconversion.

Acetonitrile was then used as the reaction solvent to compare use ofmethanesulfonyl chloride and p-toluenesulfonyl chloride. In theseexperiments, 100 mg of 2a was used at a concentration of 20 mL ofacetonitrile per gram of 2a. 2.5 equivalents of each chlorinatingreagent was used in the experiments. Each experiment was conducted byheating at 70–80° C. for 5 h and 10 min. The results are shown in Table3.

TABLE 3 Rt 2.98 5.39 8.14 8.66 11.09 12.62 RRt 0.34 0.62 0.94 1.00 1.281.46 unknown 3-Cl 4-Cl di-Cl Ratio Run Solvent Reagent 2a 15 12 3a 14 16(3a/12) 1 CH₃CN MeSO₂Cl 12.9 7.5 7.8 66.8 2.6 2.4 9.60 2 CH₃CN pTolSO₂Cl21.5 4.9 5.8 66.8 1.1 12.61Definitions

The following terms shall, for the purposes of this application, havethe respective meanings set forth below.

“Alkyl” includes linear and branched alkyl groups, e.g., methyl, ethyl,t-butyl, and the like. Preferred alkyl groups contain 1 to 3 carbonatoms.

“Aryl” alone or in combination shall include both carbocyclic andheterocyclic aromatic compounds.

“Carbocyclic aromatic solvent” shall include substituted benzenecompounds. Preferred substituents include alkyl (particularly methyl),chloro, and nitro. Preferred carbocyclic aromatic solvents includetoluene, xylene, and mesitylene.

“Inert organic solvent” means any organic solvent or combination ofsolvents that is unreactive in the reaction being conducted, and is asolvent for the reactants.

Examples of such solvents used in the various reactions of thisinvention are identified in the discussion of the reaction schemes andin the examples.

“Strong base” means a non aqueous base such as sodium-, potassium-,lithium hexamethyldisilazide, lithium diisopropyl amide, and the like.

Abbreviations

DMF N,N-dimethylformamide

THF tetrahydrofuran

MeOH methanol

Ether diethyl ether

DMSO dimethylsulfoxide

EtOAc ethyl acetate

AcOH acetic acid

Ac acetyl

Me methyl

Et ethyl

DEPBT 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one

DIPEA diisopropylethylamine

mCPBA meta-chloroperoxybenzoic acid

mCBA meta-chlorobenzoic acid

pTol paratoluene

azaindole 1H-pyrrolopyridine

7-azaindole 1H-pyrrolo[2,3-b]pyridine

Where noted above, publications and references, including but notlimited to patents and patent applications, cited in this specificationare herein incorporated by reference in their entirety in the entireportion cited as if each individual publication or reference werespecifically and individually indicated to be incorporated by referenceherein as being fully set forth. Any patent application to which thisapplication claims priority is also incorporated by reference herein inthe manner described above for publications and references.

While this invention has been described with an emphasis upon preferredembodiments, it will be obvious to those of ordinary skill in the artthat variations in the preferred devices and methods may be used andthat it is intended that the invention may be practiced otherwise thanas specifically described herein. Accordingly, this invention includesall modifications encompassed within the spirit and scope of theinvention as defined by the claims that follow.

1. A process for the preparation of a compound of the formula

wherein, R¹, R³ and R⁴ are each independently selected from the group ofH, C₁–C₆ alkyl, C₃–C₆cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl,C₂–C₆ alkynyl, halogen, cyano, phenyl, C(O)R⁵, C(O)NR⁸R⁹, OR¹⁰, SR¹¹,and NR¹²R¹³; R⁵ is independently selected from the group consisting ofH, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, and C₄–C₆ cycloalkenyl;R⁸ and R⁹ are each independently selected from the group consisting ofC₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₃–C₆ alkenyl, C₄–C₆ cycloalkenyl andC₃–C₆ alkynyl; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₃–C₆ alkenyl or the carbon-carbontriple bond of said C₃–C₆ alkynyl are not the point of attachment to thenitrogen to which R⁸ or R⁹ is attached; R¹⁰ and R¹¹ are eachindependently selected from the group consisting of C₁–C₆ alkyl, C₁–C₆alkyl substituted with one to three halogen atoms, C₃–C₆ cycloalkyl,C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl and C₃–C₆ alkynyl; provided the carbonatoms which comprise said carbon-carbon triple bond of said C₃–C₆alkynyl are not the point of attachment to the oxygen or sulfur to whichR¹⁰ or R¹¹ is attached; R¹² and R¹³ are each independently selected fromthe group consisting of H, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₃–C₆ alkenyl,C₄–C₆ cycloalkenyl and C₃–C₆ alkynyl; and C(O)R¹⁴; provided the carbonatoms which comprise the carbon-carbon double bond of said C₃–C₆alkenyl, C₄–C₆ cycloalkenyl or the carbon-carbon triple bond of saidC₃–C₆ alkynyl are not the point of attachment to the nitrogen to whichR¹² or R¹³ is attached; R¹⁴ is selected from the group consisting of H,C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl andC₂–C₆ alkynyl; R⁶ is selected from the group consisting of H, C₁–C₆alkyl, C₃–C₆ cycloalkyl, C₄–C₆ cycloalkenyl, C(O)NR¹⁶R¹⁷, benzyl, C₃–C₆alkenyl and C₃–C₆ alkynyl; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₃–C₆ alkenyl or the carbon-carbontriple bond of said C₃–C₆ alkynyl are not the point of attachment to thenitrogen to which R⁶ is attached; R¹⁶ and R¹⁷ are each independentlyselected from the group consisting of H, C₁–C₆ alkyl, C₃–C₆ cycloalkyl,C₃–C₆ alkenyl, C₅–C₆ cycloalkenyl and C₃–C₆ alkynyl; provided the carbonatoms which comprise the carbon-carbon double bond of said C₃–C₆alkenyl, C₅–C₆ cycloalkenyl or the carbon-carbon triple bond of theC₃–C₆ alkynyl are not the point of attachment to the nitrogen to whichR¹⁶ and R¹⁷ are attached; the process comprising: chlorinating acompound of the formula

with a chlorinating agent selected from one of (a) a compound of theformulaR^(a)SO₂Cl wherein R^(a) is C₁–C₄ alkyl; trifluoromethyl; phenyl ornaphthalene, which phenyl or napthalene can be substituted with one ormore H, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆cycloalkenyl, C₂–C₆ alkynyl, halogen, cyano, nitro, phenyl, C(O)R⁵,C(O)NR⁸R⁹, OR¹⁰; (b) a compound of the formulaR^(b)COCl wherein R^(b) is C₁–C₄ alkyl; trihalomethyl; C(O)R⁵; phenyl ornaphthalene, which phenyl or naphthalene can be substituted with one ormore H, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆cycloalkenyl, C₂–C₆ alkynyl, halogen, cyano, nitro, phenyl, C(O)R⁵,C(O)NR⁸R⁹, OR¹⁰; or (c) a compound of the formula

wherein R^(c) is independently C₁–C₄ alkyl; trifluoromethyl; phenyl ornaphthalene, which naphthalene is substituted with one or more H, C₁–C₆alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl, C₂–C₆alkynyl, halogen, cyano, phenyl and OR¹⁰; and wherein R^(d) is H, C₁–C₄alkyl; halogen; trifluoromethyl; phenyl or naphthalene, whichnaphthalene is substituted with one or more H, C₁–C₆ alkyl, C₃–C₆cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl, C₂–C₆ alkynyl, halogen,cyano, phenyl and OR¹⁰.
 2. The process of claim 1, wherein thechlorinating agent is R^(a)SO₂Cl.
 3. The process of claim 2, wherein thechlorinating agent is methanesulfonyl chloride.
 4. The process of claim1, wherein the chlorinating is conducted in a polar or dipolar aproticsolvent.
 5. The process of claim 3, wherein there is from about 2 to 3equivalents of methanesulfonyl chloride.
 6. The process of claim 1,wherein a concentration of the compound 2 is from about 1 to 2 M.
 7. Theprocess of claim 1, wherein the reaction is performed at a temperatureof from about 45 to 90° C.
 8. The process of claim 1, wherein R¹ and R³are H; R⁴ is H, halogen or cyano; and R⁶ is H, methyl or allyl.
 9. Aprocess for the preparation of a compound of the formula

wherein, R¹, R³ and R⁴ are each independently selected from the group ofH, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl,C₂–C₆ alkynyl, halogen, cyano, phenyl, C(O)R⁵, C(O)NR⁸R⁹, OR¹⁰, SR¹¹,and NR¹²R¹³; R⁵ is independently selected from the group consisting ofH, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, and C₄–C₆ cycloalkenyl;R⁸ and R⁹ are each independently selected from the group consisting ofC₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₃–C₆ alkenyl, C₄–C₆ cycloalkenyl andC₃–C₆ alkynyl; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₃–C₆ alkenyl or the carbon-carbontriple bond of said C₃–C₆ alkynyl are not the point of attachment to thenitrogen to which R⁸ or R⁹ is attached; R¹⁰ and R¹¹ are eachindependently selected from the group consisting of C₁–C₆ alkyl, C₁–C₆alkyl substituted with one to three halogen atoms, C₃–C₆ cycloalkyl,C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl and C₃–C₆ alkynyl; provided the carbonatoms which comprise said carbon-carbon triple bond of said C₃–C₆alkynyl are not the point of attachment to the oxygen or sulfur to whichR¹⁰ or R¹¹ is attached; R¹² and R¹³ are each independently selected fromthe group consisting of H, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₃–C₆ alkenyl,C₄–C₆ cycloalkenyl and C₃–C₆ alkynyl; and C(O)R¹⁴; provided the carbonatoms which comprise the carbon-carbon double bond of said C₃–C₆alkenyl, C₄–C₆ cycloalkenyl or the carbon-carbon triple bond of saidC₃–C₆ alkynyl are not the point of attachment to the nitrogen to whichR¹² or R¹³ is attached; R¹⁴ is selected from the group consisting of H,C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl andC₂–C₆ alkynyl; R⁶ is selected from the group consisting of H, C₁–C₆alkyl, C₃–C₆ cycloalkyl, C₄–C₆ cycloalkenyl, C(O)NR¹⁶R¹⁷, benzyl, C₃–C₆alkenyl and C₃–C₆ alkynyl; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₃–C₆ alkenyl or the carbon-carbontriple bond of said C₃–C₆ alkynyl are not the point of attachment to thenitrogen to which R⁶ is attached; R¹⁶ and R¹⁷ are each independentlyselected from the group consisting of H, C₁–C₆ alkyl, C₃–C₆ cycloalkyl,C₃–C₆ alkenyl, C₅–C₆ cycloalkenyl and C₃–C₆ alkynyl; provided the carbonatoms which comprise the carbon-carbon double bond of said C₃–C₆alkenyl, C₅–C₆ cycloalkenyl or the carbon-carbon triple bond of theC₃–C₆ alkynyl are not the point of attachment to the nitrogen to whichR¹⁶ and R¹⁷ are attached; R⁷ is selected from the group consisting ofCH₃, CH₂CH₃, CH₂CF₃ and CH₂CH₂CH₃; and R²⁰ is selected from the groupconsisting of C₁–C₆ alkyl, C₃–C₆ cycloalkyl, aryl[C₁–C₆]alkyl, and aryl;the process comprising: reacting a compound of the formula

with a chlorooxoacetate reagent of the formula

in the presence of a Lewis acid.
 10. The process of claim 9, wherein theLewis acid is aluminum trichloride present in an amount of at least fourequivalents.
 11. The process of claim 9, wherein the reaction isconducted in a solvent of dichloromethane: [C₁–C₃]nitroalkane in about a4:1 to 17:3 ratio.
 12. A process for the preparation of a compound ofthe formula

wherein R¹, R³ and R⁴ are each independently selected from the group ofH, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl,C₂–C₆ alkynyl, halogen, cyano, phenyl, C(O)R⁵, C(O)NR⁸R⁹, OR¹⁰, SR¹¹,and NR¹²R¹³; R⁵ is independently selected from the group consisting ofH, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, and C₄–C₆ cycloalkenyl;R⁸ and R⁹ are each independently selected from the group consisting ofC₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₃–C₆ alkenyl, C₄–C₆ cycloalkenyl andC₃–C₆ alkynyl; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₃–C₆ alkenyl or the carbon-carbontriple bond of said C₃–C₆ alkynyl are not the point of attachment to thenitrogen to which R⁸ or R⁹ is attached; R¹⁰ and R¹¹ are eachindependently selected from the group consisting of C₁–C₆ alkyl, C₁–C₆alkyl substituted with one to three halogen atoms, C₃–C₆ cycloalkyl,C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl and C₃–C₆ alkynyl; provided the carbonatoms which comprise said carbon-carbon triple bond of said C₃–C₆alkynyl are not the point of attachment to the oxygen or sulfur to whichR¹⁰ or R¹¹ is attached; R¹² and R¹³ are each independently selected fromthe group consisting of C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₃–C₆ alkenyl,C₄–C₆ cycloalkenyl and C₃–C₆ alkynyl; and C(O)R¹⁴; provided the carbonatoms which comprise the carbon-carbon double bond of said C₃–C₆alkenyl, C₄–C₆ cycloalkenyl or the carbon-carbon triple bond of saidC₃–C₆ alkynyl are not the point of attachment to the nitrogen to whichR¹² or R¹³ is attached; R¹⁴ is selected from the group consisting of H,C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl andC₂–C₆ alkynyl; R⁶ is selected from the group consisting of H, C₁–C₆alkyl, C₃–C₆ cycloalkyl, C₄–C₆ cycloalkenyl, C(O)NR¹⁶R¹⁷, benzyl, C₃–C₆alkenyl and C₃–C₆ alkynyl; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₃–C₆ alkenyl or the carbon-carbontriple bond of said C₃–C₆ alkynyl are not the point of attachment to thenitrogen to which R⁶ is attached; R¹⁶ and R¹⁷ are each independentlyselected from the group consisting of H, C₁–C₆ alkyl, C₃–C₆ cycloalkyl,C₃–C₆ alkenyl, C₅–C₆ cycloalkenyl and C₃–C₆ alkynyl; provided the carbonatoms which comprise the carbon-carbon double bond of said C₃–C₆alkenyl, C₅–C₆ cycloalkenyl or the carbon-carbon triple bond of theC₃–C₆ alkynyl are not the point of attachment to the nitrogen to whichR¹⁶ and R¹⁷ are attached; R⁷ is selected from the group consisting ofCH₃, CH₂CH₃, CH₂CF₃ and CH₂CH₂CH₃; R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷ andR²⁸ are each independently selected from the group consisting of H,C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl, C₂–C₆alkynyl, CR²⁹R³⁰OR³¹, C(O)R³², CR³³(OR³⁴)OR³⁵, CR³⁶NR³⁷R³⁸, C(O)OR³⁹,C(O)NR⁴⁰R⁴¹, CR⁴²R⁴³F, CR⁴⁴F₂, and CF₃; R²⁹, R³⁰ R³¹, R³², R³³, R³⁶,R⁴², R⁴³ and R⁴⁴ are each independently selected from the groupconsisting of H, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆cycloalkenyl, C₂–C₆ alkynyl and C(O)R⁴⁵; R³⁴, R³⁵ and R³⁹ are eachindependently selected from the group consisting of H, C₁–C₆ alkyl,C₃–C₆ cycloalkyl, C₃–C₆ alkenyl, C₄–C₆ cycloalkenyl, and C₃–C₆ alkynyl;provided the carbon atoms which comprise the carbon-carbon triple bondof said C₃–C₆ alkynyl are not the point of attachment to the oxygen towhich R³⁵ and R³⁹ are attached; R³⁷ and R³⁸ are each independentlyselected from the group consisting of H, C₁–C₆ alkyl, C₃–C₆ cycloalkyl,C₃–C₆ alkenyl, C₄–C₆ cycloalkenyl and C₃–C₆ alkynyl; provided the carbonatoms which comprise the carbon-carbon triple bond of said C₃–C₆ alkynylare not the point of attachment to the nitrogen to which R³⁷ and R³⁸ areattached; R⁴⁰ and R⁴¹ are each independently selected from the groupconsisting of H, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆cycloalkenyl and C₃–C₆ alkynyl; provided the carbon atoms which comprisethe carbon-carbon triple bond of said C₃–C₆ alkynyl are not the point ofattachment to the nitrogen to which R⁴⁰ and R⁴¹ are attached; R⁴⁵ isselected from the group consisting of H, C₁–C₆ alkyl, C₃–C₆ cycloalkyl,C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl, and C₂–C₆ alkynyl; Ar is selectedfrom the group consisting of

A¹, A², A³, A⁴, A⁵, B¹, B², B³, B⁴, C¹, C², C³, D¹, D² and D³ are eachselected from the group consisting of H, cyano, halogen, nitro, C₁–C₆alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl, C₂–C₆alkynyl, OR⁴⁶, NR⁴⁷R⁴⁸, SR⁴⁹, N₃ and CH(—N═N—)—CF₃; R⁴⁶ is selected fromthe group consisting of H, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl,C₄–C₆ cycloalkenyl, C₂–C₆ alkynyl; provided the carbon atoms whichcomprise the carbon-carbon triple bond of said C₃–C₆ alkynyl are not thepoint of attachment to the nitrogen to which R⁴⁶ is attached; R⁴⁷ andR⁴⁸ are each independently selected from the group consisting of H,C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₃–C₆ alkenyl, C₅–C₆ cycloalkenyl, C₃–C₆alkynyl, and C(O)R⁵¹; provided the carbon atoms which comprise thecarbon-carbon double bond of said C₅–C₆ alkenyl, C₄–C₆ cycloalkenyl, orthe carbon-carbon triple bond of said C₃–C₆ alkynyl are not the point ofattachment to the nitrogen to which R⁴⁷ and R⁴⁸ are attached; R⁴⁹ isselected from the group consisting of H, C₁–C₆ alkyl, C₃–C₆ cycloalkyl,C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl, C₃–C₆ alkynyl and C(O)R⁵⁰; providedthe carbon atoms which comprise the carbon-carbon triple bond of saidC₃–C₆ alkynyl are not the point of attachment to the sulfur to which R⁴⁷is attached; R⁵⁰ is C₁–C₆ alkyl or C₃–C₆ cycloalkyl; and R⁵¹ is selectedfrom the group consisting of H, C₁–C₆ alkyl and C₃–C₆ cycloalkyl; theprocess comprising: (a) treating a compound of the formula

with a chlorinating agent selected from one of a sulfonyl chloridereagent of the formulaR^(a)SO₂Cl wherein R^(a) is C₁–C₄ alkyl; trifluoromethyl; phenyl ornaphthalene, which phenyl or napthalene can be substituted with one ormore H, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆cycloalkenyl, C₂–C₆ alkynyl, halogen, cyano, nitro, phenyl, C(O)R⁵,C(O)NR⁸R⁹, OR¹⁰; (ii) a compound of the formulaR^(b)COCl wherein R^(b) is C₁–C₄ alkyl; trihalomethyl; C(O)R⁵; phenyl ornaphthalene, which phenyl or naphthalene can be substituted with one ormore H, C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆cycloalkenyl, C₂–C₆ alkynyl, halogen, cyano, nitro, phenyl, C(O)R⁵,C(O)NR⁸R⁹, OR¹⁰; or (iii) a compound of the formula

wherein R^(c) is independently H, C₁–C₄ alkyl; trifluoromethyl; phenylor naphthalene, which naphthalene is substituted with one or more H,C₁–C₆ alkyl, C₃–C₆ cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl, C₂–C₆alkynyl, halogen, cyano, phenyl and OR¹⁰; and wherein R^(d) is H, C₁–C₄alkyl; halogen; trifluoromethyl; phenyl or naphthalene, whichnaphthalene is substituted with one or more H, C₁–C₆ alkyl, C₃–C₆cycloalkyl, C₂–C₆ alkenyl, C₄–C₆ cycloalkenyl, C₂–C₆ alkynyl, halogen,cyano, phenyl and OR¹⁰; to give a compound of the formula

(b) reacting the compound of the formula 3 with a potassium alkoxide ofthe formulaR⁷O—K+. to give a compound of the formula

(c) treating the compound of the formula 4 with a compound of theformula

wherein R²⁰ is alkyl, cycloalkyl, arylalkyl or aryl, in the presence ofa Lewis acid to give a compound of the formula

(d) hydrolyzing the ester of the compound of the formula 5 to give acompound of the formula

(e) coupling the compound of the formula 6 with a compound of theformula

using an acyl activating reagent to give the compound of the formula 7.13. The process of claim 12, wherein the chlorination of step (a)comprises treatment with about 2 to 3 equivalents of methanesulfonyl ina polar aprotic solvent at a temperature of about 45 to 90° C.
 14. Theprocess of claim 12, wherein the Lewis acid in step (c) is aluminumtrichloride.
 15. The process of claim 12, wherein in step (c), thecompound of the formula 9 is methyl chlorooxoacetate.
 16. The process ofclaim 12, wherein the acyl activating agent in step (e) is selected fromthe group consisting of Vilsmeier reagent and oxalyl chloride.
 17. Theprocess of claim 12, wherein the coupling of step (e) comprises: (i)treating the compound of the formula 6 with Vilsmeier reagent; and (ii)treating the product from step (i) with the compound of the formula 8.18. The process of claim 12, wherein the compound of the formula 2 isprepared by a process comprising: oxidizing a compound of the formula

with an oxidizing agent to give the compound of the formula 2, or a saltthereof.
 19. The process of the claim 18, wherein the oxidizing agent inthe oxidation of step (a) is selected from the group consisting ofm-chloroperoxybenzoic acid, hydrogen peroxide, peracetic acid, hydrogenperoxide-urea reagent, magnesium monoperoxyphthalate hexahydrate, andoxone.
 20. The process of claim 19, wherein the oxidizing agent ism-chloroperoxybenzoic acid.
 21. The process of claim 20, wherein theoxidation of step (a) comprises treatment with from about 1 to 3equivalents of meta-chloroperoxybenzoic acid in ethyl acetate.
 22. Theprocess of claim 12, wherein R⁷ is CH₃O.
 23. The process of claim 22,wherein R¹, R³, R⁴ and R⁶ are H.
 24. The process of claim 23, whereinthe compound of formula 8 in step (e) is


25. A compound of the formula:


26. A compound of the formula: